ROS-triggered hydrophilicity switching synergizes with pH-responsive nanocarriers for therapy of diabetic wound

Abstract Chronic diabetic wounds are notoriously difficult to heal due to the self-perpetuating cycle of persistent inflammation and oxidative stress, while current therapies are limited by single-action mechanisms and inefficient drug delivery. This study developed a reactive oxygen species (ROS)/pH dual-responsive hydrophilicity switching intelligent hydrogel (GC-HA@ZIF-8@Cur) by integrating a zeolitic imidazolate framework-8 (ZIF-8) with a dynamically crosslinked hydrogel for synergistic therapy. The system employs inflammation-targeting hyaluronic acid (HA)-modified ZIF-8 nanoparticles (HA@ZIF-8@Cur) to encapsulate curcumin (Cur), which are embedded into a ROS-responsive hydrogel matrix formed by ultraviolet-initiated polymerization of methacrylated gelatin and lipoic acid-grafted chitosan. In the ROS microenvironment of diabetic wounds, oxidation of thioether bonds in the hydrogel to sulfoxide bonds enhanced the hydrophilicity, while acidic conditions induced pH-responsive dissociation of ZIF-8 to cascade-release Cur and Zn2+. Experiments demonstrated that GC-HA@ZIF-8@Cur hydrogel reshapes the immune microenvironment by downregulating pro-inflammatory factors (interleukin [IL]-6, tumor necrosis factor [TNF]-α), polarizing macrophages toward the M2 phenotype, and upregulating IL-10, eliminating vascular generation disorders. Additionally, Zn2+ promotes vascular endothelial growth factor (VEGF) expression, accelerating angiogenesis. This dual-responsive system achieves spatiotemporally precise drug release, concurrently addressing inflammation, oxidative stress, and vascular regeneration barriers, significantly improving diabetic wound healing efficiency (96.372 ± 0.779% wound closure at day 14). It provides a novel multi-targeted co-delivery strategy for chronic wound therapy.